, 1997) and heterologously expressed KARs (Swanson and Heinemann, 1998). These findings suggested that additional proteins might associate with native receptors and alter their gating. Over the past 20 years, tremendous progress has been made toward identifying proteins that interact with iGluRs, thus unraveling the molecular machinery that regulates the trafficking and function of iGluRs. The picture that emerges is that iGluRs are but one component of larger-scale, multimeric complexes. This is of particular interest in the context of the postsynaptic density (PSD) of excitatory synapses—a vast web of interacting proteins that comprise large and dynamic supramolecular assemblies (Scannevin and Huganir, 2000, Grant

et al., 2005 and Yamauchi, 2002: Feng and Zhang, 2009). The C-terminal tails (CTDs) of iGluRs have NVP-BKM120 nmr been a particular focus of attention IWR-1 molecular weight in this regard, because they exhibit a great deal of diversity in length and sequence, and display numerous consensus sites for phosphorylation and a variety of protein-protein interactions. A myriad of cytosolic proteins have been identified that interact with the CTDs of iGluRs

and regulate their membrane trafficking, anchoring at synapses, and involvement in intracellular signaling cascades. Depending on the particular class of iGluR, such cytoplasmic proteins include postsynaptic density-95/discs large/zona occludens-2 (PDZ) domain-containing proteins (such as GRIP/ABP, PICK1, and a variety of membrane-associated guanylate kinase or MAGUK proteins), cytoskeleton-interacting or scaffolding proteins (such as α-actinin, protein 4.1, and spectrin), and the ATPase NSF (Song and Huganir, 2002, Malinow and Malenka, 2002, Bredt and Nicoll, 2003, Collingridge et al., 2004, Kim and Sheng, 2004, Derkach et al., 2007, Lau and Zukin, 2007 and Elias and Nicoll, 2007). The CTDs of iGluRs first are also subject to phosphorylation by a variety of kinases such as protein kinase C (PKC), protein kinase A (PKA), and calcium-calmodulin kinase II (CaMKII), and by tyrosine kinases such as src and fyn (Boehm and Malinow, 2005 and Lee, 2006). The first bona fide transmembrane auxiliary subunit of

an iGluR was discovered through the characterization of stargazer, a spontaneous mutation in an inbred mouse line, originally distinguished by its striking behavioral phenotype—dyskinesia, severe ataxia, characteristic head-tossing, and frequent spike-wave discharges (SWDs), reminiscent of absence epilepsy in humans ( Noebels et al., 1990). Genetic mapping revealed that the stargazer mutation is attributable to a single recessive mutation on mouse chromosome 15 ( Letts et al., 1997). Subsequent positional cloning showed that the locus of the mutation encodes stargazin—a novel, brain-specific, low-molecular weight, tetraspanning membrane protein with homology to the voltage-gated calcium channel (VGCC) subunit γ-1, hence its alternative name, γ-2 ( Letts et al., 1998) ( Figure 2).